Long‐term functional correction of cystathionine β‐synthase deficiency in mice by adeno‐associated viral gene therapy
Year: 2021
Type: article
Abstract: Cystathionine β‐synthase (CBS) deficiency is a recessive inborn error of sulfur metabolism characterized by elevated blood levels of total homocysteine (tHcy). Patients diagnosed with CBS deficiency are currently treated by a combination of vitamin supplementation and restriction of foods containing the homocysteine precursor methionine, but the effectiveness of this therapy is limited due to poor compliance. A mouse model for CBS deficiency (Tg‐I278T Cbs−/−) was used to evaluate a potential gene therapy approach to treat CBS deficiency utilizing an AAVrh.10‐based vector containing the human CBS cDNA downstream of the constitutive, strong CAG promoter (AAVrh.10hCBS). Mice were administered a single dose of virus and followed for up to 1 year. The data demonstrated a dose‐dependent increase in liver CBS activity and a dose‐dependent decrease in serum tHcy. Liver CBS enzyme activity at 1 year was similar to Cbs+/− control mice. Mice given the highest dose (5.6 × 1011 genomes/mouse) had mean serum tHcy decrease of 97% 1 week after injection and an 81% reduction 1 year after injection. Treated mice had either full‐ or substantial correction of alopecia, bone loss, and fat mass phenotypes associated with Cbs deficiency in mice. Our findings show that AAVrh.10‐based gene therapy is highly effective in treating CBS deficiency in mice and supports additional pre‐clinical testing for eventual use human trials.
DOI: 10.1002/jimd.12437
Institutions: Fox Chase Cancer Center, Weill Cornell Medicine
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W3200466118